mortality among people who inject drugs: a …death in this group, and identify participant- and...

Bull World Health Organ 2013;91:102–123 | doi:10.2471/BLT.12.108282

Systematic reviews

102

Mortality among people who inject drugs: a systematic review and meta-analysisBradley M Mathers,a Louisa Degenhardt,b Chiara Bucello,b James Lemon,b Lucas Wiessing c & Mathew Hickman d

IntroductionPeople who use drugs, especially by injection, are at higher risk of dying from both acute and chronic diseases, many of which are related to their drug use, than people who do not use these drugs. Fatal overdose and infection with human im-munodeficiency virus (HIV) and other blood-borne viruses transmitted through shared needles and syringes are the most common causes of death in this group.1 Understanding causes of death is important when setting priorities for programmes designed to reduce deaths from the use of drugs. Longitudinal studies of people who inject drugs are critical for assessing the magnitude, nature and correlates of the risk of death in this population.

A systematic review conducted in 2004 identified 30 pro-spective studies published between 1967 and 2004 that dealt with “problematic drug users” or people who inject drugs.2 These reviews have consistently shown that the practice of injecting drugs is associated with an elevated risk of death, particularly from the complications of HIV infection, drug overdose and suicide. Since these reviews were conducted, the number of studies examining mortality among cohorts of people who inject drugs has risen substantially. This has made it possible to perform fine-grained analyses that were not feasible in earlier reviews. Furthermore, those earlier reviews did not examine the potential impact of study-level variables, variation across countries, or of participant-level variables that could affect both mortality rates and differences in causes of death, yet study-level evidence suggests that males who inject drugs may be at higher risk of dying than females and that different types of drugs are associated with different risks of

death.3–5 Findings from other reviews have also suggested that rates of death among people who are dependent on opioids are different from the rates of death observed in people who are dependent on stimulants such as cocaine and amphetamine type stimulants.3–5

In recent years the number of studies reporting on mor-tality among people who inject drugs has increased. Hence, the objective of this review was to determine the following:• overall crude mortality rates (CMRs) and excess deaths

across cohorts of people who inject drugs, by sex;• causes of death across studies, particularly from drug over-

dose and acquired immunodeficiency syndrome (AIDS); differences in mortality rates and causes of death among HIV-positive (HIV+) and HIV-negative (HIV−) people who inject drugs;

• differences in mortality rates across cohorts by geographi-cal location and country income level;

• mortality rates by type of drug injected (e.g. opioids versus stimulants);

• mortality rates during in-treatment and off-treatment periods.

MethodsIdentifying studies

A recent series of reviews identified cohort studies among opi-oid, amphetamine and cocaine users to examine mortality.3–5 In these reviews tailored search strings were used to search three electronic databases for studies published between 1980 and

Objective To systematically review cohort studies of mortality among people who inject drugs, examine mortality rates and causes of death in this group, and identify participant- and study-level variables associated with a higher risk of death.Methods Tailored search strings were used to search EMBASE, Medline and PsycINFO. The grey literature was identified through online grey literature databases. Experts were consulted to obtain additional studies and data. Random effects meta-analyses were performed to estimate pooled crude mortality rates (CMRs) and standardized mortality ratios (SMRs).Findings Sixty-seven cohorts of people who inject drugs were identified, 14 of them from low- and middle-income countries. The pooled CMR was 2.35 deaths per 100 person–years (95% confidence interval, CI: 2.12–2.58). SMRs were reported for 32 cohorts; the pooled SMR was 14.68 (95% CI: 13.01–16.35). Comparison of CMRs and the calculation of CMR ratios revealed mortality to be higher in low- and middle-income country cohorts, males and people who injected drugs that were positive for human immunodeficiency virus (HIV). It was also higher during off-treatment periods. Drug overdose and acquired immunodeficiency syndrome (AIDS) were the primary causes of death across cohorts.Conclusion Compared with the general population, people who inject drugs have an elevated risk of death, although mortality rates vary across different settings. Any comprehensive approach to improving health outcomes in this group must include efforts to reduce HIV infection as well as other causes of death, particularly drug overdose.

a The Kirby Institute, University of New South Wales, Sydney, NSW 2052, Australia.b National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia.c Scientific Division, European Monitoring Centre for Drugs and Drug Addiction, Lisbon, Portugal.d School of Social and Community Medicine, University of Bristol, Bristol, England.Correspondence to Bradley M Mathers (e-mail: [email protected]).(Submitted: 31 May 2012 – Revised version received: 26 November 2012 – Accepted: 28 November 2012 )

Systematic reviews

Bull World Health Organ 2013;91:102–123 | doi:10.2471/BLT.12.108282 103

Systematic reviewsMortality among people who inject drugsBradley M Mathers et al.

2012: Medline, EMBASE and PsycINFO. The search strings contained keywords and database-specific terms (MeSH headings, EMTREE terms and explode terms; Box 1). All results were limited to human subjects. We identified grey literature sources reporting on mortality by searching online grey literature data-bases, library databases and the web sites listed in a published technical report.6 To make sure that no relevant papers had been missed, we sent the draft lists of the papers identified through these searches to experts for their review.

For the current study we exam-ined all papers found in the reviews of drug-related mortality but selected only cohorts composed of people who in-jected opioids and other drugs. We used the strategy outlined in the preceding paragraph to further search for these

cohorts. We included in the analysis only studies of drug users that included mortality data disaggregated by partici-pants’ injecting drug use; studies were included only if more than 70% of the cohort was composed of people who injected drugs.

The searches yielded a total of 5981 studies of mortality related to the use of opioids, amphetamines and cocaine. We identified another 79 articles by search-ing the reference lists of reviews on mor-tality related to drug use. Experts pro-vided additional studies for 16 cohorts. From these 5981 articles we excluded a total of 5762: 4999 did not focus on drug dependence or mortality, 118 did not include raw data, 292 were case series, and 600 had insufficient mortality data on people who inject drugs. In total, we selected 67 cohort studies for inclusion

in the analyses (Fig. 1). These studies were further assessed using STROBE reporting guidelines.7

Data extraction

Once we had identified all studies, one of the authors (JL) extracted the data into an Excel database (Microsoft, Red-mond, United States of America) and two others rechecked them (BM, CB). This yielded the basic data set for the statistical analyses. We extracted infor-mation on the location of each study, the period of recruitment and duration of follow-up, the number of people in the cohort, the percentage of people in the cohort who injected drugs, the number of person–years (PY) of follow-up and the number of deaths.

We extracted CMRs and standard-ized mortality ratios (SMRs). We ex-

Box 1. Strategy for search of the peer-reviewed literature

Database specific search terms were developed and combined using Boolean operators as follows:

( < opioids > OR < cocaine > OR < amphetamine type stimulants > ) AND < drug use > AND < mortality > AND < longitudinal studies >

All results were limited to human subjects and publication years between 1980 and 2012. The full search strings used for each database were as follows:

Medline: ((heroin or opiate$ OR opium OR opioid$ OR Exp Opium/ OR exp Narcotics/ OR exp Heroin Dependence/ OR exp Heroin/ OR exp Morphine/ OR exp Opioid-Related Disorders/ OR exp Opiate Alkaloids/ OR exp Methadone/ OR exp Analgesics, Opioid/) OR (Cocaine exp Cocaine-Related Disorders/ or exp Cocaine/ or exp Crack Cocaine/) OR (ATS OR amphetamine type stimulant$ OR amphetamine$ OR methamphetamine OR deoxyephedrine OR desoxyephedrine OR Desoxyn OR madrine OR metamfetamine OR methamphetamine hydrochloride OR methylamphetamine OR n-methylamphetamine OR d-amphetamine OR dextroamphetamine sulfate OR dexamphetamine OR dexedrine OR dextro-amphetamine sulfate OR dextroamphetamine sulfate OR d-amphetamine sulfate OR stimulant$ exp amphetamines/ or exp amphetamine/ or exp dextroamphetamine/ or exp p-chloroamphetamine/ or exp 2,5-dimethoxy-4-methylamphetamine/ or exp p-hydroxyamphetamine/ or exp iofetamine/ or exp methamphetamine/ or exp benzphetamine/ or exp phentermine/ or exp chlorphentermine/ or exp mephentermine/ or exp amphetamine-related disorders/)) AND (drug abuse$ OR drug use$ OR drug misuse$ OR drug dependenc$ OR substance abuse$ OR substance use$ OR substance misuse$ OR substance dependenc$ OR addict$ OR Exp Substance-related disorders/) AND (Mortal$ OR fatal$ OR death$ OR exp “death and dying”/ OR exp mortality/ OR exp hospitalization) AND (“cohort” OR “longitudinal” OR “incidence” OR “prospective” OR “follow-up” OR exp cohort studies/ OR exp longitudinal studies/ OR exp follow-up studies/ OR exp prospective studies/)

EMBASE: ((heroin OR opioid$ OR opiate$ OR opium OR exp Diamorphine/ OR exp Opiate/ OR exp Methadone treatment/ OR exp Methadone/) OR (Cocaine exp Cocaine-Related Disorders/ or exp Cocaine/ or exp Crack Cocaine/) OR (ATS OR amphetamine type stimulant$ OR amphetamine$ OR methamphetamine OR deoxyephedrine OR desoxyephedrine OR Desoxyn OR madrine OR metamfetamine OR methamphetamine hydrochloride OR methylamphetamine OR n-methylamphetamine OR d-amphetamine OR dextroamphetamine sulfate OR dexamphetamine OR dexedrine OR dextro-amphetamine sulfate OR dextroamphetamine sulfate OR d-amphetamine sulfate OR stimulant$ exp amphetamines/ or exp amphetamine/ or exp dextroamphetamine/ or exp p-chloroamphetamine/ or exp 2,5-dimethoxy-4-methylamphetamine/ or exp p-hydroxyamphetamine/ or exp iofetamine/ or exp methamphetamine/ or exp benzphetamine/ or exp phentermine/ or exp chlorphentermine/ or exp mephentermine/ or exp amphetamine-related disorders/)) AND (Drug abuse OR drug use$ OR drug misuse OR drug dependenc$ OR substance abuse OR substance use$ OR substance misuse OR substance dependenc$ OR addict$ OR exp substance abuse/ OR exp drug abuse/ OR exp analgesic agent abuse/ OR exp drug abuse pattern/ OR exp drug misuse/ OR exp drug traffic/ OR exp multiple drug abuse/ OR exp addiction/ OR exp drug dependence/ OR exp cocaine dependence/ OR narcotic dependence/ OR exp heroin dependence/ OR exp morphine addiction/ OR exp opiate addiction/) AND (Mortal$ OR fatal$ OR death$ OR exp death/ OR exp “cause of death”/ OR exp accidental death/ OR exp sudden death/ OR exp fatality/ OR exp mortality/ OR exp hospitalization/) AND (“cohort” OR “longitudinal” OR “incidence” OR “prospective” OR “follow-up” OR exp cohort analysis/ OR exp longitudinal study/ OR exp prospective study/ OR exp follow up/)

PsychINFO: ((“heroin” OR “opium” OR “opiate$” OR “methadone” OR exp Opiates/ OR exp METHADONE/ OR exp HEROIN ADDICTION/ OR exp HEROIN) OR (Cocaine exp Cocaine-Related Disorders/ or exp Cocaine/ or exp Crack Cocaine/) OR (ATS OR amphetamine type stimulant$ OR amphetamine$ OR methamphetamine OR deoxyephedrine OR desoxyephedrine OR Desoxyn OR madrine OR metamfetamine OR methamphetamine hydrochloride OR methylamphetamine OR n-methylamphetamine OR d-amphetamine OR dextroamphetamine sulfate OR dexamphetamine OR dexedrine OR dextro-amphetamine sulfate OR dextroamphetamine sulfate OR d-amphetamine sulfate OR stimulant$ exp amphetamines/ or exp amphetamine/ or exp dextroamphetamine/ or exp p-chloroamphetamine/ or exp 2,5-dimethoxy-4-methylamphetamine/ or exp p-hydroxyamphetamine/ or exp iofetamine/ or exp methamphetamine/ or exp benzphetamine/ or exp phentermine/ or exp chlorphentermine/ or exp mephentermine/ or exp amphetamine-related disorders/)) AND (Drug abuse OR drug use$ OR drug misuse OR drug dependenc$ OR substance abuse OR substance use$ OR substance misuse OR substance dependenc$ OR addict$ OR Exp drug abuse/ OR exp drug addiction/ OR exp addiction/ OR exp drug usage) AND (Mortal$ OR fatal$ OR death$ OR exp “death and dying”/ OR exp mortality/ OR exp hospitalization) AND (“cohort” OR “longitudinal” OR “incidence” OR “prospective” OR “follow-up” OR Exp age differences/ OR exp cohort analysis/ OR exp human sex differences)

Note: $ indicates wildcard.


Systematic reviewsMortality among people who inject drugs Bradley M Mathers et al.

pressed CMRs as the number of deaths per 100 PY of follow-up. We reported SMRs as calculated in the source pa-pers. In several cases standard errors, confidence intervals (CIs) and CMRs were not reported, so we estimated them using standard calculations. We also put into the database CMRs and SMRs that were reported according to sex, HIV status, treatment status and type of drug injected, as well as data on deaths from drug overdose or AIDs-related causes.

We included in the analyses studies that specified treatment status if they classified the data by mutually exclusive treatment groups or periods. We only included studies in which the exact dates of entry into and exit from the study had been recorded and used to calculate the

number of PYs, the number of deaths and mortality rates.

Statistical analysis

We performed meta-analyses to estimate pooled all-cause CMRs and all-cause SMRs, and pooled estimates of deaths from specific causes, as in previous re-views.8 To perform the meta-analyses we used the “metan” command in STATA version 10.1 (StataCorp LP, College Sta-tion, USA). The “metan” command uses inverse-variance weighting to calculate random effects pooled summary esti-mates and their confidence limits, true effect differences between studies and study heterogeneity.9,10 Random effects models allow for heterogeneity between and within studies. We expected high

levels of heterogeneity between stud-ies because of the marked differences between the samples of people inject-ing drugs; accordingly, we applied a random effects model to all analyses. The appropriateness of this a priori decision was confirmed by the resultant χ2 and the I-squared statistic. To further investigate this heterogeneity, when the data permitted we divided the cohorts into subgroups and used CMR ratios to compare differences in mortality.11 We made comparisons between subgroups as follows: sex (male versus female); pri-mary drug injected at baseline (opioids versus stimulants); HIV status (HIV+ versus HIV−); and treatment for drug dependence (in-treatment period versus off-treatment period).

We examined the following as po-tential sources of heterogeneity in CMRs or SMRs using random effects univariate meta-regressions in STATA: geographic region, country income group (based on World Bank categories), percentage of sample that injected drugs, were male or were HIV+ at baseline; presence of opioid users in the cohort; and the year in which the follow-up period ended.12,13

ResultsWe included 67 cohorts in the analysis; 14 were from low- and middle-income countries (Table 1). Studies from Eu-rope, North America and Australasia were the most common; nine studies were from Asia and one was from South America. The pooled CMR across the 65 cohorts for which a CMR was provided was 2.35 deaths per 100 PY (Fig. 2). Co-horts from Asia had the highest pooled CMRs (5.25), followed by the cohorts from North America (2.64) and western Europe (2.31); cohorts from Australasia had the lowest pooled CMR (0.71).

SMRs were reported for 31 cohorts; their pooled SMR was 14.68 (Fig. 3). Since the heterogeneities (I2) of the pooled CMR and SMR were both very high (98.6% and 98.3%, respectively), we stratified estimates by subgroups.

Sex differences in mortality

Thirty-seven studies presented CMRs by s e x . 1 4 , 1 7 – 1 9 , 2 1 – 2 4 , 2 6 , 2 8 , 3 0 – 3 2 , 3 4 , 3 6 – 3 8 , 4 3 ,

45–50,52,54,57,58,62,66–72,74 The pooled CMR ratio for males versus females was 1.32 (Fig. 4), which suggests that crude mor-tality was higher among males. Nineteen studies reported SMRs by sex;14,17,21,24,

26,28,30,32,34,38,43,46,52,54,58,66,67,70,74 the pooled

Fig. 1. Flowchart showing study selection process for systematic review of studies on mortality in people who inject drugs

Total from initial search

Hand search:79

From experts:16

Not drug/mortality focused:4999

No raw data:118

Case series studies:292

Insufficient mortality data on people who inject drugs: 600

5981

6060

6076

1077

959

667

67



Tabl

e 1.

St

udie

s inc

lude

d in

this

syst

emat

ic re

view

of s

tudi

es o

n m

orta

lity a

mon

g pe

ople

who

inje

ct d

rugs

Stud

yCo

untr

yCo

untr

y in

com

eSa

mpl

ing

fram

en

Peop

le w

ho

inje

ct d

rugs

(%

)

Mal

es

(%)

Drug

(s)

used

Recr

uitm

ent

perio

dEn

d of

fo

llow

-up

perio

d

PYs o

f fo

llow

-up

CMR

95%

CISM

R95

% CI

Anto

lini e

t al. (

2006

)14Ita

lyH

igh

DTS

4644

100

79.1

O, S

1975

–199

919

9939

667

2.01

1.80

–2.1

613

.01

12.1

1–13

.91

Azim

et a

l. (20

08)15

Bang

lade

shLo

wDT

S55

210

010

0O

2002

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420

0790

1.6

6.32

4.68

–7.9

6–

–Az

im e

t al. (

2009

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ngla

desh

Low

DTS

675

100

100

O20

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46–4

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Barg

agli

et a

l. (20

01)17

Italy

Hig

hDT

S11

432

8482

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1980

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519

9780

787

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8.2

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(contin

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106 Bull World Health Organ 2013;91:102–123 | doi:10.2471/BLT.12.108282


Stud

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06)49

Italy

Hig

hDT

S12

1410

075

.5O

1977

–199

620

0213

280

.32.

041.

8–2.

3–

–M

cAnu

lty e

t al. (

1995

)50U

SAH

igh

OR,

HC

1769

100

73.3

–19

89–1

991

1992

3149

1.05

0.69

–1.4

18.

35.

71–1

1.66

Mez

zela

ni e

t al. (

1998

)51Ita

lyH

igh

DTS

6248

100

––

1991

1991

6158

.52.

912.

48–3

.33

14.2

812

.28–

16.5

6M

iller

et a

l. (20

07)52

Cana

daH

igh

SIF

572

100

53.1

O, S

1966

–200

420

0416

081.

370.

80–1

.94

16.4

9.1–

27.1

Mor

oni e

t al. (

1991

)53Ita

lyH

igh

DTS

2279

100

–O

1981

–198

819

8913

069

2.43

2.16

–2.6

9–

–M

oska

lew

icz

et a

l. (1

996)

54Po

land

Mid

dle

DTS

656

100

74.2

O19

83–1

992

1992

3594

2.28

1.81

–2.8

312

.06

9.6–

15.0

Mug

a et

al. (

2007

)55Sp

ain

Hig

hDT

S11

8110

079

.5O

1987

–200

420

0410

116

3.74

3.38

–4.1

4–

–N

yhlé

n (2

011)

56Sw

eden

Hig

hDT

S56

179

68O,

S19

70–1

978

2006

15 2

03.1

1.30

1.12

–1.4

85.

945.

5–6.

8O

’Dris

coll

et a

l. (20

01)57

USA

Hig

hDT

S, o

ther

2849

100

63.9

O, S

1994

–199

719

9745

911.

591.

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.96

––

Opp

enhe

imer

et a

l. (1

994)

58U

nite

d Ki

ngdo

mH

igh

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128

100

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O19

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9123

49.7

1.83

1.28

–2.3

811

.98.

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6.09

Qua

n et

al. (

2007

)59Th

aila

ndM

iddl

eDT

S34

610

093

.1O,

S19

9920

0257

1.4

3.85

2.42

–5.8

313

.98.

71–2

1.04

Qua

n et

al. (

2010

)60Vi

et N

amM

iddl

eDT

S89

410

010

0O

2005

2007

710.

16.

304.

60–8

.50

13.4

11.4

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3Ra

him

i-Mov

agha

r et a

l. (2

009)

61Isl

amic

Re

publ

ic o

f Ira

n

Mid

dle

DTS

7910

0–

O20

0720

0720

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830–

14.3

0–

–

Reec

e (2

010)

62Au

stra

liaH

igh

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2773

100

72.8

O20

00–2

007

2007

9362

.40.

500.

36–0

.65

––

(. . .continued)

(contin

ues.

. .)

107Bull World Health Organ 2013;91:102–123 | doi:10.2471/BLT.12.108282


Stud

yCo

untr

yCo

untr

y in

com

eSa

mpl

ing

fram

en

Peop

le w

ho

inje

ct d

rugs

(%

)

Mal

es

(%)

Drug

(s)

used

Recr

uitm

ent

perio

dEn

d of

fo

llow

-up

perio

d

PYs o

f fo

llow

-up

CMR

95%

CISM

R95

% CI

Sánc

hez-

Carb

onel

l et

al. (

2000

)63Sp

ain

Hig

hDT

S13

588

71.0

O19

8519

9512

05.9

3.4

2.36

–4.4

428

.58

14.6

5–42

.65

Seam

an e

t al. (

1998

)64U

nite

d Ki

ngdo

mH

igh

DTS

316

100

100

O19

83–1

994

1994

1416

.92.

331.

6–3.

27–

–

Solo

mon

et a

l. (20

09)65

Indi

aM

iddl

eDT

S, o

ther

1158

100

100

O20

05–2

006

2008

1998

4.25

3.35

–5.1

611

.18.

85–1

3.7

Søre

nsen

et a

l. (20

05)66

Den

mar

kH

igh

DTS

101

100

67.3

O19

80–1

984

1999

1232

.33.

492.

44–4

.53

15.7

511

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1.2

Sten

back

a et

al. (

2007

)67Sw

eden

Hig

hM

ultip

le81

783

79.2

O, S

1967

2003

22 4

68.2

2.12

1.93

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14.

383.

99–4

.78

Stoo

v et

al. (

2008

)68Au

stra

liaH

igh

OR,

SB

220

100

56.4

O, S

1990

–199

520

0631

510.

830.

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.21

––

Tait

et a

l. (20

08)69

Aust

ralia

Hig

hDT

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4≥

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59.6

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01–2

001

2005

4166

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540.

28–0

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––

van

Haa

stre

cht e

t al.

(199

6)70

Net

herla

nds

Hig

hDT

S, o

ther

509

100

61.9

O, S

1985

–199

219

9322

293.

232.

56–4

.07

24.8

19.4

1–31

.23

Vlah

ov e

t al. (

2005

)71U

SAH

igh

OR,

SB

3593

100

77.3

O, S

1988

2005

25 7

364.

504.

24–4

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––

Vlah

ov e

t al. (

2008

)72U

SAH

igh

OR,

SB

2089

100

62.3

O, S

1997

–199

920

0286

29.3

0.71

0.54

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8–

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bran

ksy

et a

l. (20

11)73

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h Re

publ

icH

igh

OR

151

100

43O,

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998

2008

1659

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480.

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9.31

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49

Zacc

arel

li et

al. (

1994

)74Ita

lyH

igh

DTS

2029

100

75.5

–19

85–1

991

1991

7872

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301.

96–2

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31.9

227

.44–

36.9

3Zh

ang

et a

l. (20

05)75

Chin

aM

iddl

eDT

S37

610

082

.8O

2002

2003

382.

47.

734.

87–1

0.6

47.6

231

.63–

68.7

1

CI, c

onfid

ence

inte

rval

, CM

R, c

rude

mor

talit

y ra

te; D

TS, d

rug

treat

men

t ser

vice

; HC,

hea

lth c

linic

; NSP

, nee

dle

and

syrin

ge p

rogr

amm

e; O

, opi

oids

; OR,

out

reac

h; P

R, H

IV p

reve

ntio

n se

rvic

e; P

Y, pe

rson

–yea

rs; S

, stim

ulan

ts; S

B, sn

owba

lling

; SIF,

supe

rvise

d in

ject

ing

faci

lity;

SM

R, st

anda

rdize

d m

orta

lity

ratio

; T&C

, HIV

test

ing

and

coun

selli

ng; U

SA, U

nite

d St

ates

of A

mer

ica.

a Not

exp

licitl

y st

ated

, but

impl

ied

in th

e pa

per.

b The

pro

porti

on o

f sub

ject

s who

inje

cted

dru

gs w

as n

ot re

porte

d bu

t was

ass

umed

to b

e at

leas

t 70%

bec

ause

of t

he p

redo

min

ance

of i

njec

ting

as a

rout

e of

adm

inist

ratio

n am

ong

opio

id-d

epen

dent

peo

ple

in th

is co

untr

y.c S

ubje

cts w

ere

follo

wed

for 5

yea

rs a

fter t

he d

ate

of e

nrol

men

t.d D

ata

on h

istor

y of

dru

g us

e w

as a

vaila

ble

for 6

2% o

f the

subj

ects

, and

of t

hese

, 99%

had

a h

istor

y of

inje

ctin

g dr

ugs.

Not

e: S

ome

CMRs

and

PYs

of f

ollo

w-u

p w

ere

calc

ulat

ed (f

orm

ulae

ava

ilabl

e fro

m th

e co

rresp

ondi

ng a

utho

r).

(. . .continued)



Fig. 2. Crude mortality rates for people who inject drugs, by region

NOTE: Weights are from random effects analysis

.

.

.

.

.

.

Overall (I−squared = 98.6%, p = 0.000)

EMCDDA 2011 (Sweden)

Asia

Bargagli 2001 (Italy)

Azim 2008 (Bangladesh)

Subtotal (I−squared = 99.4%, p = 0.000)

Zaccarelli 1994 (Italy)

Miller 2007 (Canada)

Evans 2012 (USA)

Quan 2007 (Thailand)

EMCDDA 2011 (Croatia)EMCDDA 2011 (Bulgaria)

Liu 2011 (China)

Stenbacka 2007 (Sweden)

Cohort

Moskalewicz 1996 (Poland)EMCDDA 2011 (Latvia)

Sorensen 2005 (Denmark)

Degenhardt 2009 (Australia)

Latin America

Moroni 1991 (Italy)

EMCDDA 2011 (Romania)

Solomon 2009 (India)

Tait 2008 (Australia)

Antolini 2006 (Italy)

Galli 1994 (Italy)

Muga 2007 (Spain)

Australasia

Vlahov 2008 (USA)

Reece 2010 (Australia)

Quan 2010 (Viet Nam)

Hickman 2003 (UK)

VanHaastrecht 1996 (Netherlands)


Fugelstad 1998 (Sweden)

Frischer 1997 (UK)

Rahimi-Movahgar 2009 (Islamic Republic of Iran)

Cardoso 2006 (Brazil)

Vlahov 2005 (USA)

Manfredi 2006 (Italy)

Zhang 2005 (China)

Zabransky 2011 (Czech Republic)

Davoli 2007 (Italy)

Ciccolallo 2000 (Italy)

North America

Goedert 1995 (Italy)


Brancato 1995 (Italy)

Subtotal (I−squared = .%, p = .)

Oppenheimer 1994 (UK)

Jarrin 2007 (Spain)

Goedert 2001 (USA)

Seaman 1998 (UK)

Haarr 2007 (Norway)


Mezzelani 1998 (Italy)

McAnulty 1995 (USA)

Lejckova 2007 (Czech Republic)Lumbreras 2006 (Spain)

Eskild 1993 (Norway)

Digusto 2004 (Australia)

Golz 2001 (Germany)

Fingerhood 2006 (USA)

O’Driscoll 2001 (USA)


Jafan 2010 (Islamic Republic of Iran)


Clausen 2008 (Norway)

Nyhlen 2011 (Sweden)

Esteban 2003 (Spain)

Cornish 2010 (UK)Copeland 2004 (UK)


Sanchez−Carbonell 2000 (Spain)


Bauer 2008 (Austria)

Stoove 2008 (Australia)

Eastern Europe

Western Europe

2.35 (2.12, 2.58)

3.33 (2.98, 3.68)

2.15 (2.05, 2.25)

6.32 (4.68, 7.96)

2.64 (1.25, 4.02)

2.30 (1.96, 2.63)

1.37 (0.80, 1.94)

0.91 (0.62, 1.20)

3.85 (2.42, 5.83)

1.09 (0.93, 1.25)1.18 (0.91, 1.46)

6.89 (5.79, 7.98)

2.12 (1.93, 2.31)

CMR (95% CI)

2.28 (1.81, 2.83)1.60 (1.43, 1.77)

3.49 (2.45, 4.53)

0.89 (0.86, 0.92)

2.43 (2.16, 2.69)

0.57 (0.47, 0.68)

4.25 (3.35, 5.16)

0.50 (0.29, 0.72)

2.01 (1.79, 2.16)

2.52 (2.28, 2.77)

3.74 (3.38, 4.14)

0.71 (0.54, 0.88)

0.50 (0.36, 0.65)

6.30 (4.60, 8.50)

1.61 (1.13, 2.23)

3.23 (2.56, 4.07)

2.31 (2.06, 2.56)

7.76 (5.54, 10.58)

2.08 (1.52, 2.64)

4.83 (0.00, 14.30)

2.77 (1.45, 4.09)

4.50 (4.24, 4.76)

2.04 (1.80, 2.30)

7.73 (4.87, 10.60)

0.48 (0.15, 0.81)

0.74 (0.59, 0.88)

2.26 (2.08, 2.43)

1.57 (1.41, 1.75)

3.52 (2.46, 4.59)

2.04 (1.26, 2.83)

2.77 (1.45, 4.09)

1.83 (1.28, 2.38)

2.02 (1.92, 2.12)

4.67 (4.42, 4.92)

2.33 (1.60, 3.27)

1.92 (0.95, 3.44)

5.25 (4.16, 6.35)

2.91 (2.48, 3.33)

1.05 (0.69, 1.41)

0.84 (0.75, 0.93)2.18 (2.00, 2.36)

2.77 (2.22, 3.42)

1.27 (0.40, 2.29)

4.22 (2.80, 5.64)

7.14 (5.22, 9.06)

1.59 (1.22, 1.96)

1.99 (1.72, 2.25)

4.08 (1.25, 6.91)

3.85 (2.94, 4.76)

1.95 (1.70, 2.23)

1.30 (1.12, 1.48)

3.68 (3.11, 4.25)

1.00 (0.86, 1.15)2.45 (2.06, 2.84)

1.31 (0.82, 1.80)

3.40 (2.36, 4.44)

0.71 (0.46, 0.96)

5.42 (3.45, 7.40)

0.83 (0.56, 1.21)

100.00

1.77

1.84

0.94

13.22

1.78

1.65

1.79

0.91

1.831.80

1.29

1.82

Weight

1.691.83

1.33

1.85

1.80

1.84

1.43

1.82

1.83

1.81

1.76

1.83

1.83

0.78

1.67

1.54

60.26

0.57

1.66

0.10

1.14

1.80

1.81

0.47

1.78

1.83

1.83

1.83

1.31

1.51

1.14

1.67

1.84

1.81

1.48

1.19

7.71

1.74

1.77

1.841.83

1.64

1.40

1.08

0.80

1.76

1.80

0.48

1.43

1.80

1.83

1.66

1.831.75

8.99

1.33

8.68

0.77

1.78

%

2.35 (2.12, 2.58)

3.33 (2.98, 3.68)

2.15 (2.05, 2.25)

6.32 (4.68, 7.96)

2.64 (1.25, 4.02)

2.30 (1.96, 2.63)

1.37 (0.80, 1.94)

0.91 (0.62, 1.20)

3.85 (2.42, 5.83)

1.09 (0.93, 1.25)1.18 (0.91, 1.46)

6.89 (5.79, 7.98)

2.12 (1.93, 2.31)

CMR (95% CI)

2.28 (1.81, 2.83)1.60 (1.43, 1.77)

3.49 (2.45, 4.53)

0.89 (0.86, 0.92)

2.43 (2.16, 2.69)

0.57 (0.47, 0.68)

4.25 (3.35, 5.16)

0.50 (0.29, 0.72)

2.01 (1.79, 2.16)

2.52 (2.28, 2.77)

3.74 (3.38, 4.14)

0.71 (0.54, 0.88)

0.50 (0.36, 0.65)

6.30 (4.60, 8.50)

1.61 (1.13, 2.23)

3.23 (2.56, 4.07)

2.31 (2.06, 2.56)

7.76 (5.54, 10.58)

2.08 (1.52, 2.64)

4.83 (0.00, 14.30)

2.77 (1.45, 4.09)

4.50 (4.24, 4.76)

2.04 (1.80, 2.30)

7.73 (4.87, 10.60)

0.48 (0.15, 0.81)

0.74 (0.59, 0.88)

2.26 (2.08, 2.43)

1.57 (1.41, 1.75)

3.52 (2.46, 4.59)

2.04 (1.26, 2.83)

2.77 (1.45, 4.09)

1.83 (1.28, 2.38)

2.02 (1.92, 2.12)

4.67 (4.42, 4.92)

2.33 (1.60, 3.27)

1.92 (0.95, 3.44)

5.25 (4.16, 6.35)

2.91 (2.48, 3.33)

1.05 (0.69, 1.41)

0.84 (0.75, 0.93)2.18 (2.00, 2.36)

2.77 (2.22, 3.42)

1.27 (0.40, 2.29)

4.22 (2.80, 5.64)

7.14 (5.22, 9.06)

1.59 (1.22, 1.96)

1.99 (1.72, 2.25)

4.08 (1.25, 6.91)

3.85 (2.94, 4.76)

1.95 (1.70, 2.23)

1.30 (1.12, 1.48)

3.68 (3.11, 4.25)

1.00 (0.86, 1.15)2.45 (2.06, 2.84)

1.31 (0.82, 1.80)

3.40 (2.36, 4.44)

0.71 (0.46, 0.96)

5.42 (3.45, 7.40)

0.83 (0.56, 1.21)

100.00

1.77

1.84

0.94

13.22

1.78

1.65

1.79

0.91

1.831.80

1.29

1.82

1.691.83

1.33

1.85

1.80

1.84

1.43

1.82

1.83

1.81

1.76

1.83

1.83

0.78

1.67

1.54

60.26

0.57

1.66

0.10

1.14

1.80

1.81

0.47

1.78

1.83

1.83

1.83

1.31

1.51

1.14

1.67

1.84

1.81

1.48

1.19

7.71

1.74

1.77

1.841.83

1.64

1.40

1.08

0.80

1.76

1.80

0.48

1.43

1.80

1.83

1.66

1.831.75

8.99

1.33

8.68

0.77

1.78

%

0−10 −5 5 10 15

Image produced using Stata (StataCorp. LP, College Station, TX, United States of America).CI, confidence interval; CMR, crude mortality rate.



CMR ratio suggests that females had significantly greater excess mortality than males in similar age groups in the general population (Fig. 5). Only two of the nineteen studies presented SMRs for males that were greater than those for females.30,74

Causes of death

Several studies reported specific causes of death. The pooled CMR for death from drug overdose was 0.62 per 100 PY across 43 studies (Fig. 6). Eleven stud-ies reported CMRs for death from drug overdose by sex: overall the CMR was

1.38 times higher (Fig. 7) among males than among females.14,17,19,21,24,32,38,49,52,57,58

In 20 studies CMRs were pro-vided separately for people who inject drugs according to their HIV sta-tus.15,16,18,28,34,36–40,45,48,49,55,57,60,65,70,72,74 All-cause mortality was three times higher among HIV+ than among HIV− sub-jects (CMR ratio: 3.15) (Fig. 8). Much of this elevated mortality appeared to result from AIDS deaths among HIV+ users of injecting drugs. The pooled estimate of AIDS-related mor-tality for the 16 studies for which data were available was 2.55 per 100 PY

(Fig. 9).28,33–36,38–41,48,49,60,65,70,72,74 When we examined mortality from causes other than AIDS, we found it to be 1.63 times higher among HIV+ than among HIV− people who inject drugs (Fig. 10).28,34,36,38–40,48,49,60,65,70,72,74

Mortality from drug overdose was presented by HIV status in 9 stud-ies.28,34,36,38,39,49,65,70,74 Pooled estimates showed mortality to be twice as high among HIV+ than among HIV− people who inject drugs (CMR ratio: 1.99) (Fig. 11). Further analyses across 13 studies conducted on HIV+ people who inject drugs showed no significant

Fig. 3. Standardized mortality ratios for people who inject drugs, by region


.

.

.

.

.



Cohort

Frischer 1997 (UK)



Moskalewicz 1996 (Poland)Subtotal (I−squared = 87.7%, p = 0.000)

EMCDDA 2011 (Croatia)





Asia




Australasia


McAnulty 1995 (USA)


EMCDDA 2011 (Latvia)


Lejckova 2007 (Czech Republic)




Western Europe

Sorensen 2005 (Denmark)Sanchez−Carbonell 2000 (Spain)




Galli 1994 (Italy)

Zhang 2005 (China)



Eastern Europe

Copeland 2004 (UK)

Subtotal (I−squared = .%, p = .)


North America

Ferri 2007 (Italy)

14.68 (13.01, 16.35)

17.30 (16.50, 18.20)

SMR (95% CI)

22.00 (16.50, 28.80)

5.94 (5.50, 6.80)

11.19 (3.58, 18.80)

12.06 (9.60, 15.00)9.25 (7.22, 11.28)

10.30 (8.90, 12.00)

16.40 (9.10, 27.10)

24.80 (19.41, 31.23)

17.52 (14.62, 20.43)

6.50 (5.40, 7.70)

14.28 (12.28, 16.56)

11.90 (8.64, 16.09)

4.38 (3.99, 4.78)

31.00 (24.60, 37.40)

8.30 (5.71, 11.66)

13.40 (11.40, 15.30)

9.00 (8.00, 10.00)

14.47 (9.95, 19.00)

8.15 (7.28, 9.09)

27.60 (24.90, 30.70)

14.40 (9.31, 19.49)

6.40 (6.20, 6.60)

15.75 (11.40, 21.20)28.58 (14.65, 42.65)

11.10 (8.85, 13.70)

31.92 (27.44, 36.93)

13.01 (11.38, 13.09)

20.50 (20.02, 24.33)

47.62 (31.63, 68.71)

30.70 (17.30, 44.00)

13.90 (8.71, 21.04)

17.45 (14.59, 20.30)

6.40 (6.20, 6.60)

29.13 (19.27, 44.04)

7.77 (6.70, 8.95)

100.00

4.08

Weight

2.65

4.10

5.53

3.7215.82

3.98

1.88

2.72

63.51

4.05

3.86

3.42

4.12

2.57

3.65

3.91

4.07

11.02

4.08

3.67

2.98

4.12

3.041.06

3.80

3.09

4.08

3.86

0.68

1.13

2.64

3.68

4.12

1.26

4.05

%

14.68 (13.01, 16.35)

17.30 (16.50, 18.20)

SMR (95% CI))

22.00 (16.50, 28.80)

5.94 (5.50, 6.80)

11.19 (3.58, 18.80)

12.06 (9.60, 15.00)9.25 (7.22, 11.28)

10.30 (8.90, 12.00)

16.40 (9.10, 27.10)

24.80 (19.41, 31.23)

17.52 (14.62, 20.43)

6.50 (5.40, 7.70)

14.28 (12.28, 16.56)

11.90 (8.64, 16.09)

4.38 (3.99, 4.78)

31.00 (24.60, 37.40)

8.30 (5.71, 11.66)

13.40 (11.40, 15.30)

9.00 (8.00, 10.00)

14.47 (9.95, 19.00)

8.15 (7.28, 9.09)

27.60 (24.90, 30.70)

14.40 (9.31, 19.49)

6.40 (6.20, 6.60)

15.75 (11.40, 21.20)28.58 (14.65, 42.65)

11.10 (8.85, 13.70)

31.92 (27.44, 36.93)

13.01 (11.38, 13.09)

20.50 (20.02, 24.33)

47.62 (31.63, 68.71)

30.70 (17.30, 44.00)

13.90 (8.71, 21.04)

17.45 (14.59, 20.30)

6.40 (6.20, 6.60)

29.13 (19.27, 44.04)

7.77 (6.70, 8.95)

100.00

4.08

2.65

4.10

5.53

3.7215.82

3.98

1.88

2.72

63.51

4.05

3.86

3.42

4.12

2.57

3.65

3.91

4.07

11.02

4.08

3.67

2.98

4.12

3.041.06

3.80

3.09

4.08

3.86

0.68

1.13

2.64

3.68

4.12

1.26

4.05

%

0−68.7 0 68.7

Image produced using Stata (StataCorp. LP, College Station, TX, United States of America).CI, confidence interval; SMR, standardized mortality ratio.



difference in deaths from drug overdose and from AIDS in this group (CMR ratio: 1.35; P = 0.554) (Fig. 12).28,33–36,38,

39,41,49,65,70,71,74

Only four studies presented data by sex and HIV status.37,47,49,74 They showed no significant difference in CMRs be-tween HIV+ males and HIV+ females who inject drugs (CMR ratio: 1.13; Fig. 13), but HIV– males had a pooled CMR 1.81 times greater than that of HIV– females who inject drugs (Fig. 14).

Mortality by primary drug injected at baseline

Five studies estimated mortality by primary drug injected (opioids versus

stimulants) (Table 2). Pooled estimates of all-cause mortality by primary type of drug injected showed no overall dif-ference across studies (CMR ratio: 1.25; 95% CI: 0.60–2.61; P = 0.553).36,46,57,70,71 The same was true of studies of mortal-ity resulting from drug overdose (CMR ratio: 1.85; 95% CI: 0.75–4.56; P = 0.18). In three of the four studies mortality as-sociated with drug overdose was higher among people injecting opioids than among those injecting stimulants.36,46,71 In the fourth study, people who injected primarily stimulants had higher rates of drug overdose; however, the deaths from overdose in this group were later shown to have been caused by opioid use.57

Mortality according to treatment

Six studies provided information on mortality during in-treatment and off-treatment periods at follow-up: the meta-analysis suggested that mortality was 2.52 times higher during off-treat-ment periods than during in-treatment periods (Fig. 15).22,23,25,26,35,37

Heterogeneity in mortality

We performed univariate analyses to determine if the heterogeneity in overall CMRs and SMRs could be explained by participant characteristics and method-ological variables. The results showed that high-income countries had lower

Fig. 4. Ratios of crude mortality rates in males versus females who inject drugs





Ferri 2007 (Italy)

Lumbreras 2006 (Spain)

Galli 1994 (Italy)


Cohort



Stoove 2008 (Australia)Tait 2008 (Australia)



Vlahov 2008 (USA)

Copeland 2004 (UK)


McAnulty 1995 (USA)

Moskalewicz 1996 (Poland)


Lejckova 2007 (Czech Republic)Liu 2011 (China)

Jarrin 2007 (Spain)


Evans 2012 (USA)

Vlahov 2005 (USA)


Frischer 1997 (UK)



Hickman 2003 (UK)








Cornish 2010 (UK)

1.32 (1.21, 1.44)

1.58 (1.47, 1.70)

1.32 (1.09, 1.61)

1.51 (1.06, 2.16)

1.50 (1.21, 1.86)

1.14 (0.89, 1.45)

0.86 (0.45, 1.64)

RR (95% CI)

1.74 (0.93, 3.26)

1.14 (0.86, 1.51)

3.49 (1.32, 9.22)1.09 (0.43, 2.76)

1.24 (0.98, 1.56)

1.30 (1.09, 1.55)

1.21 (0.73, 1.99)

1.23 (0.87, 1.74)

1.14 (0.44, 3.01)

1.59 (0.66, 3.84)

1.80 (1.00, 3.23)

0.68 (0.37, 1.24)

1.88 (1.44, 2.45)0.80 (0.39, 1.66)

1.36 (1.19, 1.55)

1.35 (0.99, 1.84)

1.60 (0.76, 3.37)

1.20 (1.04, 1.38)

0.97 (0.86, 1.09)

0.99 (0.57, 1.72)

1.14 (0.85, 1.53)

2.57 (1.56, 4.24)

2.01 (0.78, 5.18)

3.31 (1.31, 8.36)

1.22 (0.86, 1.74)

1.08 (0.70, 1.67)

1.42 (0.87, 2.32)

2.62 (1.18, 5.81)

0.64 (0.27, 1.53)

1.10 (0.68, 1.78)

1.67 (1.16, 2.40)

100.00

6.03

4.76

3.06

4.56

4.19

1.41

Weight

1.48

3.77

0.710.77

4.35

4.98

2.04

3.13

0.72

0.85

1.63

1.58

3.951.17

5.50

3.52

1.12

5.39

5.63

1.77

3.68

2.05

0.75

0.77

3.09

2.44

%

2.11

1.01

0.88

2.15

2.99

1.32 (1.21, 1.44)

1.58 (1.47, 1.70)

1.32 (1.09, 1.61)

1.51 (1.06, 2.16)

1.50 (1.21, 1.86)

1.14 (0.89, 1.45)

0.86 (0.45, 1.64)

RR (95% CI

1.74 (0.93, 3.26)

1.14 (0.86, 1.51)

3.49 (1.32, 9.22)1.09 (0.43, 2.76)

1.24 (0.98, 1.56)

1.30 (1.09, 1.55)

1.21 (0.73, 1.99)

1.23 (0.87, 1.74)

1.14 (0.44, 3.01)

1.59 (0.66, 3.84)

1.80 (1.00, 3.23)

0.68 (0.37, 1.24)

1.88 (1.44, 2.45)0.80 (0.39, 1.66)

1.36 (1.19, 1.55)

1.35 (0.99, 1.84)

1.60 (0.76, 3.37)

1.20 (1.04, 1.38)

0.97 (0.86, 1.09)

0.99 (0.57, 1.72)

1.14 (0.85, 1.53)

2.57 (1.56, 4.24)

2.01 (0.78, 5.18)

3.31 (1.31, 8.36)

1.22 (0.86, 1.74)

1.08 (0.70, 1.67)

1.42 (0.87, 2.32)

2.62 (1.18, 5.81)

0.64 (0.27, 1.53)

1.10 (0.68, 1.78)

1.67 (1.16, 2.40)

100.00

6.03

4.76

3.06

4.56

4.19

1.41

1.48

3.77

0.710.77

4.35

4.98

2.04

3.13

0.72

0.85

1.63

1.58

3.951.17

5.50

3.52

1.12

5.39

5.63

1.77

3.68

2.05

0.75

0.77

3.09

2.44

%

2.11

1.01

0.88

2.15

2.99

1.5 2 3 4

Image produced using Stata (StataCorp. LP, College Station, TX, United States of America).CI, confidence interval; RR, relative risk.



CMRs than low- and middle-income countries (Fig. 16). Cohorts with greater proportions of males and HIV+ partici-pants at baseline also had higher CMRs. Cohorts whose follow-up periods ended in more recent years had lower SMRs (Table 3). Study data were not sufficient to allow for multivariate analyses.

DiscussionAlthough previous reviews have exam-ined mortality among people who inject drugs, to our knowledge this is the most comprehensive systematic review of the topic and the first to employ novel approaches to search for the available evidence. These approaches ranged from standard searches of the peer-reviewed literature to comprehensive searches of the non-peer reviewed literature and multiple expert consultations, as well as examination of both participant- and study-level factors potentially associated with the risk of death.

The pooled CMR of 2.35 deaths per 100 PY provides evidence of the

high mortality associated with injecting drug use. The pooled SMR of 14.68 also shows that mortality is much higher in those who inject drugs than in the general population. Differences by sex were evident: across all studies that reported mortality by sex, males had higher CMRs, yet females who inject drugs had a much higher elevation in mortality relative to their age-matched peers in the general population than did males who inject drugs.

Most of the cohorts identified were from 14 high-income countries; togeth-er these 14 counties represent 78% of the total estimated population of people who inject drugs in such countries.76 Studies from only 11 low or middle income countries were identified; these countries account for only 40% of the estimated number of people inject-ing drugs in low- or middle-income countries.76

Although pooled CMRs were higher among people injecting drugs in low- and middle-income countries rather than high-income countries, we

observed no significant difference in pooled SMRs. This suggests that the higher CMRs may reflect higher over-all mortality in the general population in low- and middle-income countries than in high-income countries. The lowest and highest mortality rates were documented in cohorts in Australasia and Asia, respectively. Differences across high-income countries probably reflect differences in HIV infection prevalence, coverage of HIV prevention and cov-erage of opioid agonist maintenance treatment.76,77

Drug overdose and AIDS-related mortality were by far the most com-mon causes of death. The pooled CMR for death from drug overdose was 0.62 per 100 PY, higher among males than females who inject drugs, and higher among HIV+ people who inject drugs than among those who were HIV−. In three of the four studies comparing drug overdose among people injecting opioids compared to those injecting stimulants, CMRs were higher among the former group, as expected.36,46,71 In

Fig. 5. Ratios of standardized mortality ratios for males versus females who inject drugs



Ferri 2007 (Italy)


Hickman 2003 (UK)





Cohort



Frischer 1997 (UK)







Copeland 2004 (UK)

Galli 1994 (Italy)


0.58 (0.49, 0.69)

0.29 (0.21, 0.42)

0.81 (0.42, 1.53)

0.95 (0.37, 2.45)

0.60 (0.47, 0.75)

1.44 (1.01, 2.05)

1.05 (0.64, 1.73)

0.55 (0.31, 0.99)

0.79 (0.49, 1.29)

0.68 (0.63, 0.73)

0.43 (0.25, 0.74)

0.24 (0.10, 0.57)

0.60 (0.50, 0.71)

0.50 (0.41, 0.61)

0.99 (0.76, 1.29)

0.37 (0.20, 0.67)

0.43 (0.28, 0.67)

0.67 (0.47, 0.95)

0.36 (0.28, 0.46)

0.41 (0.36, 0.46)

100.00

5.68

3.66

2.30

6.60

5.70

4.60

4.00

Weight

4.68

7.40

4.21

2.60

6.94

6.83

6.35

3.93

5.06

5.74

6.50

7.24

0.58 (0.49, 0.69)

0.29 (0.21, 0.42)

0.81 (0.42, 1.53)

0.95 (0.37, 2.45)

0.60 (0.47, 0.75)

1.44 (1.01, 2.05)

1.05 (0.64, 1.73)

0.55 (0.31, 0.99)

RR (95% CI)

0.79 (0.49, 1.29)

0.68 (0.63, 0.73)

0.43 (0.25, 0.74)

0.24 (0.10, 0.57)

0.60 (0.50, 0.71)

0.50 (0.41, 0.61)

0.99 (0.76, 1.29)

0.37 (0.20, 0.67)

0.43 (0.28, 0.67)

0.67 (0.47, 0.95)

0.36 (0.28, 0.46)

0.41 (0.36, 0.46)

100.00

5.68

3.66

2.30

6.60

5.70

4.60

4.00

4.68

%

7.40

4.21

2.60

6.94

6.83

6.35

3.93

5.06

5.74

6.50

7.24

1.5 1.5




a fourth study, however, drug overdose was higher among people who injected stimulants,57 although further inves-tigation revealed that the deaths from overdose in this group were more often linked to the injection of opioids than to the injection of stimulants. This find-ing highlights the fact that people who inject drugs often use more than one drug type, even if they have a particular drug of choice.

The prevalence of HIV infection varied widely. As expected, overall mor-tality was much higher among HIV+ than among HIV− people who inject drugs (pooled CMR ratio: 3.15), but

mortality from causes other than AIDS was also higher among those who were HIV+. Overdose-related mortality was also higher among HIV+ people who inject drugs in many cohorts. These differences in mortality may reflect dif-ferences in risky behaviour, physical health and social disadvantage.

The observational evidence exam-ined in this review is consistent with the evidence from randomized controlled trials that opioid agonist maintenance treatment is associated with a reduced risk of death.78 Among cohorts for which in-treatment and off-treatment periods were carefully tracked, mortality rates

were around 2.5 times higher in off-treatment periods than in in-treatment periods. Variation in exposure to treat-ment could also explain differences between cohorts in mortality from drug overdose, although this variation was not explicitly measured across cohorts.

The prevention of HIV transmis-sion among people who inject drugs is clearly a public health priority.79,80 There is growing evidence that opioid agonist maintenance treatment, antiretrovi-ral treatment and needle and syringe programmes reduce HIV transmis-sion.81–83 These interventions have been implemented in many countries, but

Fig. 6. Crude mortality rates for death from drug overdose in people who inject drugs






Frischer 1997 (UK)



Goedert 2001 (USA)


van Haastrecht 1996 (Netherlands)Vlahov 2005 (USA)



Seaman 1998 (UK)Quan 2007 (Thailand)





Vlahov 2008 (USA)




Hickman 2003 (UK)

Galli 1994 (Italy)

Copeland 2004 (UK)

Zhang 2005 (China)


Moroni 1991 (Italy)



Davoli 2007 (Italy)

Cohort

Eskild 1993 (Norway)Ferri 2007 (Italy)



Jarrin 2007 (Spain)


McAnulty 1995 (USA)


Haarr 2007 (Norway)




0.62 (0.53, 0.70)

0.12 (0.00, 0.29)

0.69 (0.60, 0.80)

0.05 (0.02, 0.08)

0.98 (0.63, 1.45)

0.30 (0.23, 0.37)

1.03 (0.84, 1.22)

0.64 (0.55, 0.74)

1.10 (0.64, 1.56)

0.72 (0.41, 1.17)0.71 (0.61, 0.82)

0.76 (−0.10, 1.62)

0.14 (0.03, 0.26)

1.41 (0.86, 2.18)0.89 (0.11, 1.67)

0.44 (0.26, 0.75)

0.97 (0.78, 1.15)

0.45 (0.34, 0.56)

0.77 (0.46, 1.22)

0.31 (0.21, 0.46)

0.18 (0.14, 0.23)

0.81 (0.30, 1.76)

0.52 (0.47, 0.57)

1.01 (0.58, 1.44)

0.92 (0.77, 1.07)

0.61 (0.43, 0.83)

4.71 (2.53, 6.88)

2.06 (0.84, 3.27)

0.93 (0.77, 1.12)

1.69 (0.73, 2.65)

0.30 (0.22, 0.39)

0.40 (0.09, 0.72)

CMR (95% CI)

1.85 (1.37, 2.33)0.46 (0.39, 0.56)

0.61 (0.53, 0.69)

0.55 (0.40, 0.74)

0.32 (0.28, 0.36)

0.80 (0.30, 1.30)

0.41 (0.22, 0.71)

2.30 (1.64, 3.10)

1.22 (0.32, 2.12)

0.70 (0.48, 0.98)

0.43 (0.41, 0.45)

0.25 (0.07, 0.64)

100.00

3.04

3.21

3.35

1.83

3.28

2.85

3.22

1.63

1.963.19

%

0.71

3.15

1.060.83

2.58

2.88

3.16

1.95

3.12

3.33

0.91

3.32

1.73

3.04

2.79

0.14

0.40

2.94

0.60

3.25

2.24

Weight

1.573.24

3.27

2.94

3.34

1.50

2.58

0.91

0.66

2.54

3.36

2.39

0.62 (0.53, 0.70)

0.12 (0.00, 0.29)

0.69 (0.60, 0.80)

0.05 (0.02, 0.08)

0.98 (0.63, 1.45)

0.30 (0.23, 0.37)

1.03 (0.84, 1.22)

0.64 (0.55, 0.74)

1.10 (0.64, 1.56)

0.72 (0.41, 1.17)0.71 (0.61, 0.82)

0.76 (−0.10, 1.62)

0.14 (0.03, 0.26)

1.41 (0.86, 2.18)0.89 (0.11, 1.67)

0.44 (0.26, 0.75)

0.97 (0.78, 1.15)

0.45 (0.34, 0.56)

0.77 (0.46, 1.22)

0.31 (0.21, 0.46)

0.18 (0.14, 0.23)

0.81 (0.30, 1.76)

0.52 (0.47, 0.57)

1.01 (0.58, 1.44)

0.92 (0.77, 1.07)

0.61 (0.43, 0.83)

4.71 (2.53, 6.88)

2.06 (0.84, 3.27)

0.93 (0.77, 1.12)

1.69 (0.73, 2.65)

0.30 (0.22, 0.39)

0.40 (0.09, 0.72)

CMR (95% CI

1.85 (1.37, 2.33)0.46 (0.39, 0.56)

0.61 (0.53, 0.69)

0.55 (0.40, 0.74)

0.32 (0.28, 0.36)

0.80 (0.30, 1.30)

0.41 (0.22, 0.71)

2.30 (1.64, 3.10)

1.22 (0.32, 2.12)

0.70 (0.48, 0.98)

0.43 (0.41, 0.45)

0.25 (0.07, 0.64)

100.00

3.04

3.21

3.35

1.83

3.28

2.85

3.22

1.63

1.963.19

%

0.71

3.15

1.060.83

2.58

2.88

3.16

1.95

3.12

3.33

0.91

3.32

1.73

3.04

2.79

0.14

0.40

2.94

0.60

3.25

2.24

1.573.24

3.27

2.94

3.34

1.50

2.58

0.91

0.66

2.54

3.36

2.39

0−2 0 2 4 6




often on a limited scale only.77 Clearly, however, AIDS is only one of several common causes of death in this group: a comprehensive approach to improving health outcomes among people who inject drugs must also include efforts to reduce other causes of death frequently found among them, particularly drug overdose.84

Limitations of the evidence

Evidence on mortality rates among users of injecting drugs is still predominantly from high-income countries, particu-larly in western Europe. Interestingly, however, this review has shown that despite marked differences in CMRs across countries, the extent to which this mortality exceeds that of the general population may show less pronounced differences. It would be inappropriate to assume that mortality is equally high among all people who inject drugs. New research in this area is needed, especially

Fig. 7. Ratios of crude mortality rates for death from drug overdose in males versus females who inject drugs



Ferri 2007 (Italy)




Galli 1994 (Italy)



Copeland 2004 (UK)

Cohort




1.38 (1.08, 1.76)

0.65 (0.36, 1.17)

1.41 (1.07, 1.85)

0.63 (0.16, 2.40)

1.84 (1.23, 2.74)

1.03 (0.70, 1.54)

3.00 (1.29, 6.97)

1.49 (0.69, 3.22)

1.05 (0.53, 2.08)

1.91 (0.56, 6.59)

3.36 (0.35, 32.19)

1.83 (1.27, 2.64)

100.00

9.88

17.94

2.82

14.29

14.32

6.07

6.94

8.16

Weight

3.27

1.08

15.22

1.38 (1.08, 1.76

0.65 (0.36, 1.17)

1.41 (1.07, 1.85)

0.63 (0.16, 2.40)

1.84 (1.23, 2.74)

1.03 (0.70, 1.54)

3.00 (1.29, 6.97)

1.49 (0.69, 3.22)

1.05 (0.53, 2.08)

RR (95% CI)

1.91 (0.56, 6.59)

3.36 (0.35, 32.19)

1.83 (1.27, 2.64)

100.00

9.88

17.94

2.82

14.29

14.32

6.07

6.94

8.16

3.27

1.08

15.22

%

1.5 5

Image produced using Stata (StataCorp. LP, College Station, TX, United States of America).CI, confidence interval, RR, relative risk.

Fig. 8. Ratios of crude mortality rates in HIV-positive versus HIV-negative people who inject drugs




Cohort



Frischer 1997 (UK)






Galli 1994 (Italy)





Jarrin 2007 (Spain)


Goedert 2001 (USA)

Vlahov 2008 (USA)


Muga 2007 (Spain)

3.15 (2.78, 3.58)

3.75 (2.84, 4.95)

2.24 (1.46, 3.43)

3.31 (1.63, 6.70)

3.53 (1.55, 8.05)

2.93 (1.94, 4.44)

2.18 (1.58, 2.99)

2.48 (0.92, 6.67)

5.31 (3.75, 7.53)

10.00 (5.59, 17.88)

2.41 (1.98, 2.94)

4.08 (2.26, 7.38)

3.62 (2.27, 5.79)

3.56 (2.04, 6.21)

3.02 (2.54, 3.60)

3.35 (3.00, 3.75)

1.38 (0.74, 2.57)

3.47 (3.11, 3.86)

2.46 (1.18, 5.12)

0.42 (0.06, 3.02)

2.91 (2.24, 3.77)

100.00

7.08

Weight

4.86

2.50

1.96

5.01

6.42

1.44

5.95

3.32

8.50

3.23

4.37

3.52

8.89

9.85

3.00

9.92

2.36

0.40

7.41

3.15 (2.78, 3.58)

3.75 (2.84, 4.95)

RR (95% CI)

2.24 (1.46, 3.43)

3.31 (1.63, 6.70)

3.53 (1.55, 8.05)

2.93 (1.94, 4.44)

2.18 (1.58, 2.99)

2.48 (0.92, 6.67)

5.31 (3.75, 7.53)

10.00 (5.59, 17.88)

2.41 (1.98, 2.94)

4.08 (2.26, 7.38)

3.62 (2.27, 5.79)

3.56 (2.04, 6.21)

3.02 (2.54, 3.60)

3.35 (3.00, 3.75)

1.38 (0.74, 2.57)

3.47 (3.11, 3.86)

2.46 (1.18, 5.12)

0.42 (0.06, 3.02)

2.91 (2.24, 3.77)

100.00

7.08

4.86

2.50

1.96

5.01

6.42

1.44

5.95

3.32

8.50

3.23

4.37

3.52

8.89

9.85

3.00

9.92

2.36

0.40

7.41

%

1.5 2 4 6

Image produced using Stata (StataCorp. LP, College Station, TX, United States of America).CI, confidence interval; HIV, human immunodeficiency virus; RR, relative risk.



Fig. 9. Crude mortality rates for AIDS-related deaths in people injecting drugs who were HIV-positive at baseline




Cohort

Vlahov 2008 (USA)



van Haastrecht 1996 (Netherlands)

Galli 1994 (Italy)

Goedert 2001 (USA)




Frischer 1997 (UK)

Golz 2001 (Germany)





2.55 (1.81, 3.28)

0.62 (0.01, 1.23)

1.24 (0.25, 2.23)

8.64 (3.94, 13.34)

1.94 (1.69, 2.20)

1.71 (0.74, 2.68)

2.97 (2.36, 3.58)

9.12 (8.13, 10.10)

0.39 (0.10, 0.68)

0.48 (0.26, 0.70)

2.73 (2.28, 3.17)

3.41 (−0.45, 7.27)

1.74 (0.83, 2.65)

2.83 (2.25, 3.42)

3.91 (2.48, 5.33)

3.37 (1.61, 5.14)

1.73 (1.43, 2.02)

100.00

7.11

Weight

6.57

1.84

7.40

6.61

7.10

6.59

7.38

7.42

7.27

2.44

6.70

7.13

5.84

5.22

7.38

2.55 (1.81, 3.28)

0.62 (0.01, 1.23)

CMR (95% CI)

1.24 (0.25, 2.23)

8.64 (3.94, 13.34)

1.94 (1.69, 2.20)

1.71 (0.74, 2.68)

2.97 (2.36, 3.58)

9.12 (8.13, 10.10)

0.39 (0.10, 0.68)

0.48 (0.26, 0.70)

2.73 (2.28, 3.17)

3.41 (−0.45, 7.27)

1.74 (0.83, 2.65)

2.83 (2.25, 3.42)

3.91 (2.48, 5.33)

3.37 (1.61, 5.14)

1.73 (1.43, 2.02)

100.00

7.11

%

6.57

1.84

7.40

6.61

7.10

6.59

7.38

7.42

7.27

2.44

6.70

7.13

5.84

5.22

7.38

0−5 0 5 10

Image produced using Stata (StataCorp. LP, College Station, TX, United States of America).AIDS, acquired immunodeficiency syndrome; CI, confidence interval; CMR, crude mortality rate; HIV, human immunodeficiency virus.

Fig. 10. Ratios of crude mortality rates for non-AIDS-related deaths in HIV-positive versus HIV-negative people who inject drugs





Galli 1994 (Italy)

Cohort

Vlahov 2008 (USA)


Frischer 1997 (UK)







Goedert 2001 (USA)

1.63 (1.28, 2.08)

1.96 (1.38, 2.78)

1.52 (0.87, 2.65)

1.15 (0.94, 1.40)

)

0.62 (0.30, 1.29)

2.66 (1.66, 4.25)

1.77 (0.78, 4.02)

0.57 (0.42, 0.79)

1.83 (1.21, 2.77)

1.98 (1.67, 2.36)

3.77 (2.11, 6.74)

2.80 (2.12, 3.70)

1.96 (1.28, 3.01)

1.31 (1.18, 1.46)

100.00

8.31

6.58

9.38

Weight

5.26

7.30

4.68

8.55

7.75

9.51

6.38

8.85

7.65

9.81

1.63 (1.28, 2.08)

1.96 (1.38, 2.78)

1.52 (0.87, 2.65)

1.15 (0.94, 1.40)

RR (95% CI

0.62 (0.30, 1.29)

2.66 (1.66, 4.25)

1.77 (0.78, 4.02)

0.57 (0.42, 0.79)

1.83 (1.21, 2.77)

1.98 (1.67, 2.36)

3.77 (2.11, 6.74)

2.80 (2.12, 3.70)

1.96 (1.28, 3.01)

1.31 (1.18, 1.46)

100.00

8.31

6.58

9.38

5.26

7.30

4.68

8.55

7.75

9.51

6.38

%

8.85

7.65

9.81

1.5 2 3 4

Image produced using Stata (StataCorp. LP, College Station, TX, United States of America).AIDS, acquired immunodeficiency syndrome; CI, confidence interval; HIV, human immunodeficiency virus; RR, relative risk.



Fig. 11. Ratios of crude mortality rates for death from drug overdose in HIV-positive versus HIV-negative people who inject drugs



Cohort


Galli 1994 (Italy)

Frischer 1997 (UK)







1.99 (1.31, 3.04)

2.18 (0.92, 5.16)

1.04 (0.70, 1.56)

2.41 (0.58, 10.05)

3.51 (2.33, 5.28)

3.90 (1.36, 11.18)

3.63 (1.32, 9.94)

2.09 (1.14, 3.83)

2.02 (1.18, 3.45)

0.77 (0.43, 1.38)

100.00

Weight

9.88

14.57

5.74

14.52

8.22

8.58

12.50

13.24

12.75

1.99 (1.31, 3.04)

RR (95% CI)

2.18 (0.92, 5.16)

1.04 (0.70, 1.56)

2.41 (0.58, 10.05)

3.51 (2.33, 5.28)

3.90 (1.36, 11.18)

3.63 (1.32, 9.94)

2.09 (1.14, 3.83)

2.02 (1.18, 3.45)

0.77 (0.43, 1.38)

100.00

9.88

14.57

5.74

14.52

8.22

8.58

12.50

13.24

12.75

%

1.5 2 4 6


Fig. 12. Ratios of crude mortality rates for AIDS-related death versus death from drug overdose in HIV-positive people who inject drugs




Vlahov 2005 (USA)





Galli 1994 (Italy)

van Haastrecht 1996 (Netherlands)

Golz 2001 (Germany)




Cohort

Frischer 1997 (UK)

1.35 (0.79, 2.31)

3.56 (2.29, 5.53)

1.70 (1.42, 2.04)

1.75 (0.74, 4.13)

1.81 (1.13, 2.88)

5.08 (3.34, 7.72)

0.20 (0.07, 0.56)

3.13 (2.06, 4.73)

1.20 (0.52, 2.76)

2.00 (0.81, 4.93)

0.18 (0.10, 0.32)

0.17 (0.08, 0.38)

4.83 (2.02, 11.57)

1.50 (0.26, 8.76)

100.00

8.56

8.99

7.39

8.51

8.61

6.84

8.62

7.47

7.24

8.25

7.57

7.34

Weight

4.60

1.35 (0.79, 2.31)

3.56 (2.29, 5.53)

1.70 (1.42, 2.04)

1.75 (0.74, 4.13)

1.81 (1.13, 2.88)

5.08 (3.34, 7.72)

0.20 (0.07, 0.56)

3.13 (2.06, 4.73)

1.20 (0.52, 2.76)

2.00 (0.81, 4.93)

0.18 (0.10, 0.32)

0.17 (0.08, 0.38)

4.83 (2.02, 11.57)

RR (95% CI)

1.50 (0.26, 8.76)

100.00

8.56

8.99

7.39

8.51

8.61

6.84

8.62

7.47

7.24

8.25

7.57

7.34

%

4.60

1.0719 1 13.9

Image produced using Stata (StataCorp. LP, College Station, TX, United States of America).AIDS, acquired immunodeficiency syndrome; CI, confidence interval; HIV, human immunodeficiency virus; RR, relative risk.



in countries where drug injecting is taking place but little research has been conducted about it.

In this review we found no signifi-cant differences in the risk of death by type of primary drug injected. This con-trasts with the findings of other reviews of people dependent on different drug types, which, despite their own limita-tions, have suggested differences in mortality among opioid-, amphetamine- and cocaine-dependent persons.3–5 An

explanation for this discrepancy might lie in the extent of drug injection among the groups examined, whether people used multiple drugs (polydrug use be-ing the norm), or the possibility, seldom examined, that some people in the co-horts switched from one primary drug to another during the follow-up period. All of these factors would have reduced our capacity to detect any differences in mortality among people injecting differ-ent types of drugs.

The ability to detect differences in mortality in cohort studies according to HIV status is subject to limitations. HIV status was typically measured at baseline only, and some subjects who contracted HIV infection during follow-up would remain assigned to the HIV− group for the entire follow-up period. Nonethe-less, this would only serve to underesti-mate the relative differences in mortality between HIV+ and HIV− people who inject drugs. The markedly higher all-

Fig. 14. Ratios of crude mortality rates in HIV-negative males versus HIV-negative females who inject drugs





Cohort


1.81 (1.06, 3.09)

2.14 (0.77, 5.93)

1.46 (0.62, 3.44)

2.02 (0.79, 5.15)

100.00

27.67

39.31

Weight

33.02

1.81 (1.06, 3.09)

2.14 (0.77, 5.93)

1.46 (0.62, 3.44)

RR (95% CI

2.02 (0.79, 5.15)

100.00

27.67

39.31

33.02

%

1.5 2 4


Fig. 13. Ratios of crude mortality rates in HIV-positive males versus HIV-positive females who inject drugs





Liu 2011 (China)

Cohort


1.13 (0.96, 1.32)

1.22 (0.89, 1.68)

1.30 (0.89, 1.91)

1.01 (0.81, 1.26)

1.45 (0.65, 3.23)

100.00

25.88

17.50

52.62

Weight

3.99

1.13 (0.96, 1.32)

1.22 (0.89, 1.68)

1.30 (0.89, 1.91)

1.01 (0.81, 1.26)

RR (95% CI)

1.45 (0.65, 3.23)

100.00

25.88

17.50

%

52.62

3.99

1.5 3




Tabl

e 2.

Co

mpa

rison

of r

isk o

f dyi

ng fr

om a

ll ca

uses

and

from

dru

g ov

erdo

se a

mon

g pe

ople

inje

ctin

g op

ioid

s and

thos

e in

ject

ing

stim

ulan

ts

Stud

yUs

ers o

f opi

oids

User

s of s

timul

ants

All-c

ause

CMR

ratio

Over

dose

CMR

ratio

Opio

id u

se d

efini

-tio

nSt

imul

ant u

se d

efi-

nitio

nPY

All-

caus

e de

aths

(N

o.)

All-

caus

e CM

Ra

Deat

hs

from

OD

(N

o.)

OD

CMRa

PYAl

l-ca

use

deat

hs

(No.

)

All-

caus

e CM

Ra

Deat

hs

from

OD

(N

o.)

OD

CMRa

Ratio

b95

% CI

Ratio

b95

% CI

Fuge

lstad

et

al.

(199

7)36

3022

.713

34.

4072

1.67

3938

390.

9915

0.38

4.44

3.12

–6.3

34.

393.

46–5

.53

Hos

pita

l rec

ords

– a

t le

ast o

nce

had

a di

agno

sis o

f her

oin

depe

nden

ce –

opio

id

user

Hos

pita

l rec

ords

–

if ha

d no

her

oin

depe

nden

ce

diag

nosis

and

at

leas

t onc

e ha

d a

diag

nosis

of A

TS

depe

nden

ceLe

jcko

va e

t al

. (20

07)46

13 3

23.9

114

0.86

360.

2797

48.4

480.

498

0.08

1.74

1.24

–2.4

43.

292.

35–4

.61

ICD

-10

code

F11

op

ioid

dep

ende

nce

ICD

-10

code

F1

5 –

stim

ulan

t de

pend

ence

O’D

risco

ll et

al.

(200

1)57

2984

.940

1.34

190.

6454

4.6

142.

577

1.29

0.52

0.29

–0.9

50.

500.

20–1

.24

Prim

ary

drug

–

hero

inPr

imar

y dr

ug –

co

cain

e or

spee

d

van

Haa

stre

cht

et a

l. (1

996)

70

268

93.

36–

–32

615

4.60

––

0.73

0.33

–1.6

4–

–M

ain

drug

inje

cted

–

hero

inM

ain

drug

inje

cted

–

coca

ine

or A

TS

Vlah

ov e

t al

. (20

05)71

2047

854.

1516

0.78

3727

175

4.70

200.

540.

880.

69–1

.14

1.44

1.12

–1.8

6H

eroi

nAn

y co

cain

e or

cra

ck

Pool

ed

esti

mat

e–

––

––

––

––

–1.

25c

0.60

–2.6

11.

85d

0.75

–4.5

6–

–

CI, c

onfid

ence

inte

rval

; CM

R, cr

ude

mor

talit

y ra

te; IC

D-1

0, In

tern

atio

nal C

lass

ifica

tion

of D

iseas

es; O

D, o

verd

ose;

PY,

pers

on–y

ears

; S, s

timul

ant.

a Dea

ths p

er 1

00 P

Y of

follo

w-u

p.b R

epre

sent

s the

CM

R ra

tio fo

r peo

ple

inje

ctin

g op

ioid

s (nu

mer

ator

) ver

sus p

eopl

e in

ject

ing

stim

ulan

ts (d

enom

inat

or).

c Met

a-an

alys

is of

all-

caus

e CM

R ra

tio: T

est o

f est

imat

e = 1;

P = 0.

553;

het

erog

enei

ty (χ

2 ) = 67

.99;

P <

0.00

05; I2 =

94.1

%.

d Met

a-an

alys

is of

ove

rdos

e CM

R ra

tio: T

est o

f est

imat

e = 1:

P = 0.

18; h

eter

ogen

eity

(χ2 ) =

20.1

0; P

< 0.

0005

; I2 = 85

.1%

.N

ote:

Val

ues r

epor

ted

in p

aper

s app

ear i

n pl

ain

text

; ital

icize

d va

lues

wer

e de

rived

from

oth

er a

vaila

ble

data

.



cause mortality that we observed among HIV+ people who inject drugs is there-fore probably a conservative estimate of the elevation in mortality in that group. Misattribution of cause of death as either AIDS- or non-AIDS-related could have occurred as well.

Treatment for HIV infection has improved greatly and has become more widely available. In some cohorts, mor-tality was examined for the periods be-fore and after highly active antiretroviral therapy (HAART) was introduced. The findings suggest that mortality among HIV+ people who inject drugs decreased after the widespread introduction of

HAART.55 Unfortunately, we were un-able to examine the impact of treatment for HIV infection across studies because mortality was rarely reported separately for the periods before and after the in-troduction of HAART.77 However, the observed association between cohorts with more recent follow-up periods and lower SMRs might have to do with the greater availability in recent years of ef-fective interventions for the prevention and treatment of HIV infection.

Reporting quality was poor. Few studies met criteria in consensus state-ments for the reporting of observational studies.7 Mortality estimates were re-

ported in various forms, including odds ratios, relative risks, hazard ratios and CMRs. Most studies did not report SMRs and many failed to report standard parameters such as PY, or were seldom easy to calculate, particularly for disag-gregated mortality estimates. As a result, only a subset of studies could be included in many of the analyses.

Causes of death were not uniformly or consistently coded. Deaths from drug overdose might have been missed in countries with limited capacity to conduct toxicological tests or where recording a death as being from a drug overdose is surrounded by stigma. As a result, we may have underestimated CMRs and SMRs for death from drug overdose. Misattribution of deaths by HIV status may have occurred, since most cohorts were assessed for HIV status at the beginning of the study only and people infected during follow-up could have been missed. Again, this may have resulted in conservative estimates of mortality among HIV+ people who inject drugs and in lower effect sizes. In future research, assessing individuals’ HIV status at several time points during the follow-up period would allow a more accurate measurement of mortality in relation to HIV status.

Fig. 15. Ratios of crude mortality rates in people who inject drugs during in-treatment period versus off-treatment period






Cornish 2010 (UK)

Cohort

Davoli 2007 (Italy)


2.52 (1.59, 4.00)

1.19 (0.58, 2.45)

2.55 (1.15, 5.66)

1.92 (1.79, 2.05)

1.90 (1.40, 2.59)

10.86 (7.25, 16.26)

1.96 (1.50, 2.56)

100.00

13.37

12.49

19.85

18.32

17.30

18.67

2.52 (1.59, 4.00)

1.19 (0.58, 2.45)

2.55 (1.15, 5.66)

1.92 (1.79, 2.05)

1.90 (1.40, 2.59)

RR (95% CI)

10.86 (7.25, 16.26)

1.96 (1.50, 2.56)

100.00

13.37

12.49

19.85

18.32

Weight

17.30

18.67

%

1 5 10 15


Table 3. Univariate associations between study-level variables and all-cause crude mortality rates (CMRs) and standardized mortality ratios (SMRs)

Characteristic CMR SMR

n t P n t P

Geographic region 53 −1.05 0.298 23 0.74 0.466Country income 67 3.03 0.004 33 0.65 0.519Percentage of cohort who inject drugs 60 1.49 0.141 26 2.04 0.052Percentage of males 57 3.40 0.001 31 0.29 0.771Percentage of cohort HIV+ at baseline 30 2.42 0.022 9 1.00 0.349Presence of people using opioids (alone or with other drugs) in cohort

67 −0.07 0.945 33 −1.28 0.209

Year in which follow-up ceased 59 0.26 0.795 32 −2.80 0.009



Fig. 16. Crude mortality rates for people who inject drugs, by country income group


.

.Overall (I−squared = 98.6%, p = 0.000)

Moroni 1991 (Italy)


Cornish 2010 (UK)


Vlahov 2005 (USA)





Cardoso 2006 (Brazil)

Liu 2011 (China)




Evans 2012 (USA)

Zhang 2005 (China)






EMCDDA 2011 (Latvia)


Sanchez−Carbonell 2000 (Spain)

Copeland 2004 (UK)



Muga 2007 (Spain)

Hickman 2003 (UK)Haarr 2007 (Norway)


Seaman 1998 (UK)


Cohort




Manfredi 2006 (Italy)McAnulty 1995 (USA)




high income

Galli 1994 (Italy)

Davoli 2007 (Italy)

Golz 2001 (Germany)


low and middle income




Frischer 1997 (UK)

Esteban 2003 (Spain)








Rahimi-Movahgar 2009 (Islamic Republic of Iran)

Jafan 2010 (Islamic Republic of Iran)


Vlahov 2008 (USA)

Goedert 2001 (USA)




EMCDDA 2011 (Bulgaria)

Jarrin 2007 (Spain)

2.35 (2.12, 2.58)

2.43 (2.16, 2.69)

2.12 (1.93, 2.31)

1.00 (0.86, 1.15)

2.91 (2.48, 3.33)

4.50 (4.24, 4.76)

6.32 (4.68, 7.96)

7.14 (5.22, 9.06)

1.57 (1.41, 1.75)

2.04 (1.26, 2.83)

2.77 (1.45, 4.09)

6.89 (5.79, 7.98)

1.27 (0.40, 2.29)

5.42 (3.45, 7.40)

2.30 (1.96, 2.63)

0.91 (0.62, 1.20)

7.73 (4.87, 10.60)

7.76 (5.54, 10.58)

3.85 (2.42, 5.83)

2.26 (2.08, 2.43)

2.28 (1.81, 2.83)

1.59 (1.22, 1.96)

1.60 (1.43, 1.77)

3.33 (2.98, 3.68)

3.40 (2.36, 4.44)

2.45 (2.06, 2.84)

3.53 (2.81, 4.24)

3.23 (2.56, 4.07)

3.74 (3.38, 4.14)

1.61 (1.13, 2.23)1.92 (0.95, 3.44)

0.84 (0.75, 0.93)

2.33 (1.60, 3.27)

0.57 (0.47, 0.68)

0.48 (0.15, 0.81)

3.52 (2.46, 4.59)

1.37 (0.80, 1.94)

2.04 (1.80, 2.30)1.05 (0.69, 1.41)

1.99 (1.72, 2.25)

3.49 (2.45, 4.53)

4.25 (3.35, 5.16)

2.52 (2.28, 2.77)

0.74 (0.59, 0.88)

4.22 (2.80, 5.64)

1.83 (1.28, 2.38)

2.77 (2.22, 3.42)

0.50 (0.29, 0.72)

2.15 (2.05, 2.25)

2.08 (1.52, 2.64)

3.68 (3.11, 4.25)

0.83 (0.56, 1.21)

2.01 (1.79, 2.16)

1.95 (1.70, 2.23)

1.09 (0.93, 1.25)

0.50 (0.36, 0.65)

6.30 (4.60, 8.50)

2.18 (2.00, 2.36)

4.83 (0.00, 14.30)

4.08 (1.25, 6.91)

1.30 (1.12, 1.48)

0.71 (0.54, 0.88)

4.67 (4.42, 4.92)

3.85 (2.94, 4.76)

0.89 (0.86, 0.92)

2.17 (1.92, 2.42)

1.18 (0.91, 1.46)

2.02 (1.92, 2.12)

100.00

1.80

1.82

1.83

1.74

1.80

0.94

0.80

1.83

1.51

1.14

1.29

1.40

0.77

1.78

1.79

0.47

0.57

0.91

1.83

1.69

1.76

1.83

1.77

1.33

1.75

16.01

1.54

1.76

1.671.19

1.84

1.48

1.84

1.78

1.31

1.65

1.811.77

1.80

1.33

1.43

1.81

1.83

1.08

1.67

1.64

1.82

1.84

1.66

1.66

1.78

1.83

1.80

1.83

1.83

0.78

1.83

0.10

0.48

1.83

1.83

1.81

1.43

1.85

83.99

1.80

1.84

2.35 (2.12, 2.58)

2.43 (2.16, 2.69)

2.12 (1.93, 2.31)

1.00 (0.86, 1.15)

2.91 (2.48, 3.33)

4.50 (4.24, 4.76)

6.32 (4.68, 7.96)

7.14 (5.22, 9.06)

1.57 (1.41, 1.75)

2.04 (1.26, 2.83)

2.77 (1.45, 4.09)

6.89 (5.79, 7.98)

1.27 (0.40, 2.29)

5.42 (3.45, 7.40)

2.30 (1.96, 2.63)

0.91 (0.62, 1.20)

7.73 (4.87, 10.60)

7.76 (5.54, 10.58)

3.85 (2.42, 5.83)

2.26 (2.08, 2.43)

2.28 (1.81, 2.83)

1.59 (1.22, 1.96)

1.60 (1.43, 1.77)

3.33 (2.98, 3.68)

3.40 (2.36, 4.44)

2.45 (2.06, 2.84)

3.53 (2.81, 4.24)

3.23 (2.56, 4.07)

3.74 (3.38, 4.14)

1.61 (1.13, 2.23)1.92 (0.95, 3.44)

0.84 (0.75, 0.93)

2.33 (1.60, 3.27)

0.57 (0.47, 0.68)

CMR (95% CI)

0.48 (0.15, 0.81)

3.52 (2.46, 4.59)

1.37 (0.80, 1.94)

2.04 (1.80, 2.30)1.05 (0.69, 1.41)

1.99 (1.72, 2.25)

3.49 (2.45, 4.53)

4.25 (3.35, 5.16)

2.52 (2.28, 2.77)

0.74 (0.59, 0.88)

4.22 (2.80, 5.64)

1.83 (1.28, 2.38)

2.77 (2.22, 3.42)

0.50 (0.29, 0.72)

2.15 (2.05, 2.25)

2.08 (1.52, 2.64)

3.68 (3.11, 4.25)

0.83 (0.56, 1.21)

2.01 (1.79, 2.16)

1.95 (1.70, 2.23)

1.09 (0.93, 1.25)

0.50 (0.36, 0.65)

6.30 (4.60, 8.50)

2.18 (2.00, 2.36)

4.83 (0.00, 14.30)

4.08 (1.25, 6.91)

1.30 (1.12, 1.48)

0.71 (0.54, 0.88)

4.67 (4.42, 4.92)

3.85 (2.94, 4.76)

0.89 (0.86, 0.92)

2.17 (1.92, 2.42)

1.18 (0.91, 1.46)

2.02 (1.92, 2.12)

100.00

1.80

1.82

1.83

1.74

1.80

0.94

0.80

1.83

1.51

1.14

1.29

1.40

0.77

1.78

1.79

0.47

0.57

0.91

1.83

1.69

1.76

1.83

1.77

1.33

1.75

16.01

1.54

1.76

1.671.19

1.84

1.48

1.84

Weight

1.78

1.31

1.65

1.811.77

1.80

1.33

1.43

1.81

1.83

1.08

1.67

1.64

1.82

1.84

1.66

1.66

1.78

1.83

1.80

1.83

1.83

0.78

1.83

0.10

0.48

1.83

1.83

1.81

1.43

1.85

83.99

1.80

1.84

%

0−10 −5 5 10 15




摘要药物注射人群的死亡率：系统回顾和荟萃分析目的系统回顾药物注射人群死亡率的队列研究，检查该群体的死亡率和死亡原因，并确定与较高死亡风险相关的参与水平和研究水平变量。方法使用定制的搜索字符串搜索EMBASE、Medline和PsycINFO。通过网上灰色文献数据库识别灰色文献。咨询专家以获取更多的研究和数据。执行随机效果荟萃分析来估计汇集的粗死亡率（CMR）和标准化死亡率（SMR）。结果确定67 个药物注射人群队列，其中14 个来自中低收入国家。汇集的CMR为每100 人年2.35 例死亡（95%置信区间，CI：2.12-2.58）。报告32 个队列的SMR；汇

集的SMR为14.68（95% CI：13.01-16.35）。CMR的比较和CMR比率的计算表明，中低收入国家的队列、男性以及艾滋病毒（HIV）呈阳性的药物注射人群中的死亡率较高。治疗结束期间死亡率也较高。药物过量和艾滋病（AIDS）是各个队列的主要死亡原因。结论尽管不同环境中的死亡率各异，与普通人群相比，药物注射人群的死亡风险更高。任何改善该群体的健康疗效的综合方案都必须包括减少艾滋病毒感染以及其他死亡致因（尤其是药物过量）的努力。

Limitations of the review and meta-analysis

Our review has limitations. The lag time between the date when the studies were conducted and when they were published in peer-reviewed journals was generally long. In light of this we used several methods to search for published and unpublished studies. We reviewed primarily English-language papers, although we also reviewed the abstracts of non-English-language peer-reviewed articles when they were available in English. When studies seemed relevant, we had them translated; we engaged ex-perts from a range of different countries and language groups to review these

reference lists. Meta-analytical methods were originally developed to aggregate the findings of randomized controlled trials,85 which have the advantage of allowing for control or adjustment of pre-conditions and sample-related fac-tors that could influence the outcomes of interest. Controlling for such factors is not possible in observational studies, like the ones included in our review.

ConclusionPeople who inject drugs have a much higher risk of death than those who do not. Major causes of death in this group are often poorly specified, but death from drug overdose is common, as is

AIDS-related mortality in settings with a high prevalence of HIV infection. HIV+ people who inject drugs have higher mortality not just from HIV-related causes but also from drug overdose. Mortality varies by participant- and study-level characteristics, which sug-gests that multiple factors contribute to the higher risk of death observed in people who inject drugs. Many of these factors are probably modifiable, since certain predominant causes of death ac-count for most of the mortality observed in this group. ■

Competing interests: None declared.

ملخصمعدل الوفيات بني األشخاص الذين يتعاطون املخدرات عن طريق احلقن: استعراض منهجي وحتليل وصفي

الغرض استعراض الدراسات األترابية املعنية بمعدل الوفيات بني املخدرات عن طريق احلقن عىل نحو يتعاطون الذين األشخاص منهجي، ودراسة معدالت الوفيات وأسباب الوفاة يف هذه الفئة، بارتفاع املرتبطة والدراسة املشاركني مستوى متغريات وحتديد

خطر الوفاة.قواعد يف للبحث خمصصة بحث عبارات استخدام تم الطريقة حتديد وتم .PsycINFOو Medlineو EMBASE بيانات غري الكتابات بيانات قواعد خالل من الرسمية غري الكتابات للحصول اخلرباء استشارة وتم اإلنرتنت. شبكة عىل الرسمية الوصفية التحليالت إجراء وتم إضافية. وبيانات دراسات عىل املجمعة األولية الوفيات معدالت لتقييم العشوائية للتأثريات

.)SMRs( ونسب الوفيات املوحدة )CMRs(الذين األشخاص من جمموعة وستني سبع حتديد تم النتائج يتعاطون املخدرات عن طريق احلقن، أربع عرشة منها من البلدان املنخفضة واملتوسطة الدخل. وكان معدل الوفيات األويل املجمع 95 %، فاصل الثقة 100 شخص-سنة )فاصل 2.35 وفاة لكل الثقة: 2.12 إىل 2.58(. وتم اإلبالغ عن نسب الوفيات املوحدة

14.68 املوحدة الوفيات نسبة وكانت جمموعة؛ وثالثني الثنتني مقارنة وأظهرت .)16.35 إىل 13.01 :% 95 الثقة )فاصل الوفيات معدالت نسب وحساب األولية الوفيات معدالت واملتوسطة املنخفضة البلدان يف الوفيات معدل ارتفاع األولية الدخل بني املجموعات والذكور واألشخاص اإلجيابيني لفريوس العوز املناعي البرشي )HIV( الذين تعاطوا املخدرات عن طريق العالج. وقف فرتات خالل كذلك مرتفعًا املعدل وكان احلقن. املكتسب املناعي العوز ومتالزمة املخدرات جرعة فرط وكان

)األيدز( السببني الرئيسيني للوفاة بني املجموعات.الذين األشخاص يتعرض السكان، بعامة مقارنة االستنتاج يتعاطون املخدرات عن طريق احلقن خلطر وفاة مرتفع، عىل الرغم أن وجيب املختلفة. البيئات بني الوفيات معدالت تفاوت من يتضمن أي هنج شامل لتحسني حصائل الصحة يف هذه الفئة جهودًا باإلضافة البرشي املناعي العوز بفريوس اإلصابة خلفض عدوى

إىل غريها من أسباب الوفاة، والسيام فرط جرعة املخدرات.



Résumé

Mortalité chez les personnes qui s’injectent des drogues : revue systématique et méta-analyseObjectif Examiner systématiquement les études de cohortes de la mortalité chez les toxicomanes par injection, étudier les taux de mortalité et les causes de décès dans ce groupe, et identifier les variables, au niveau des participants et des études, associées à un risque accru de décès.Méthodes Des critères de recherche spécifiquement adaptés ont été utilisés pour les recherches réalisées sur EMBASE, Medline et PsycINFO. La littérature grise a été identifiée par le biais de bases de données de littérature grise disponibles en ligne. Des experts ont été consultés pour obtenir des données et des études supplémentaires. Des méta-analyses des effets aléatoires ont été réalisées afin d’estimer les taux bruts de mortalité (TBM) groupés et les taux de mortalité standardisés (TMS).Résultats Soixante-sept cohortes de personnes qui s’injectent des drogues ont été identifiées, dont 14 appartenant à des pays à revenu faible et intermédiaire. Le TBM groupé était de 2,35 décès pour 100 personnes-années (intervalle de confiance de 95%, IC: 2,12 – 2,58).

Les TMS étaient indiqués pour 32 cohortes, avec un TMS groupé de 14,68 (IC de 95%: 13,01 – 16,35). La comparaison des TBM et le calcul des taux de TMS ont révélé une mortalité plus élevée parmi les cohortes des pays à revenu faible et intermédiaire, les sujets masculins et les toxicomanes par injection séropositifs. Elle était également plus élevée pendant les périodes d’interruption thérapeutique. L’overdose et le syndrome d’immunodéficience acquise (SIDA) étaient les causes principales des décès parmi ces cohortes.Conclusion Si l’on compare avec la population globale, les personnes qui s’injectent des drogues ont un risque élevé de décès, bien que les taux de mortalité varient selon les contextes. Toute approche exhaustive visant à améliorer les résultats de ce groupe en matière de santé doit comprendre des efforts en vue de diminuer l’infection par le VIH, ainsi que d’autres causes de décès, notamment l’overdose.

Резюме

Смертность среди лиц, вводящих наркотики внутривенно: систематический обзор и мета-анализЦель Провести систематический обзор когортных исследований смертности среди лиц, вводящих наркотики внутривенно, изучить уровни смертности и причины смерти в данной группе и определить переменные на уровне участников и исследований, связанные с высоким риском смерти.Методы Поиск исследований осуществлялся по базам данных EMBASE, Medline и PsycINFO по специализированным критериям поиска. Поиск литературы для служебного пользования осуществлялся по онлайновым базам данных литературы для служебного пользования. С целью получения дополнительных данных и исследований проводились консультации с экспертами. Для определения суммарных общих показателей смертности (ОПС) и стандартизированных коэффициентов смертности (СКС) выполнялся мета-анализ случайных эффектов.Результаты Были выявлены шестьдесят семь когорт лиц, вводящих наркотики внутривенно, 14 из которых относятся к странам с низким и средним уровнями доходов. Суммарный ОПС составлял 2,35 смертей на 100 человеко-лет (95% доверительный

интервал, ДИ: 2,12–2,58). СКС фиксировался для 32 когорт; суммарный СКС составлял 14,68 (95% ДИ: 13,01-16,35). Сравнение ОПС и расчет коэффициентов ОПС выявил высокий уровень смертности в когортах, относящихся к странам с низким и средним уровнями доходов, среди мужчин и лиц, вводивших наркотики внутривенно, которые имели положительные результаты на вирус иммунодефицита человека (ВИЧ). Высокий уровень также отмечен вне периодов лечения. Передозировка наркотиков и синдром приобретенного иммунодефицита (СПИД) являлись основными причинами смерти в когортах.Вывод По сравнению с населением в целом, лица, вводящие наркотики внутривенно, подвержены повышенному риску смерти несмотря на то, что уровни смертности варьируются в зависимости от условий. Любой комплексный подход к улучшению результатов мероприятий по охране здоровья в данной группе должен включать в себя меры по сокращению уровня ВИЧ-инфекции, а также других причин смерти, в особенности, передозировки наркотиков.

Resumen

La mortalidad entre consumidores de drogas inyectables: una revisión sistemática y meta-análisisObjetivo Revisar de forma sistemática los estudios de cohortes sobre la mortalidad entre los consumidores de drogas inyectables, examinar las tasas de mortalidad y las causas de muerte en este grupo e identificar las variables relacionadas con el estudio y los participantes asociadas a un mayor riesgo de muerte.Métodos Se emplearon cadenas de búsqueda adaptadas para registrar EMBASE, Medline y PsycINFO. La literatura gris se identificó por medio de bases de datos de literatura gris en línea. Se consultaron expertos a fin de obtener datos y estudios adicionales y se llevaron a cabo metaanálisis de efectos aleatorios para calcular las tasas brutas combinadas de mortalidad y las tasas de mortalidad estandarizadas.Resultados Se identificaron diecisiete cohortes de consumidores de drogas inyectables, 14 de las cuales en países con ingresos bajos y medios. La tasa bruta combinada de mortalidad fue de 2,35 fallecimientos por cada 100 años-persona (intervalo de confianza del 95%, IC: 2,12-2,58). Se declararon las tasas de mortalidad estandarizadas

para 32 cohortes; la tasa bruta combinada de mortalidad fue de 14,68 (IC 95%: 13,01-16,35). La comparación de las tasas brutas combinadas de mortalidad y el cálculo de las proporciones de la mortalidad bruta combinada revelaron que la mortalidad fue superior en las cohortes de países con ingresos bajos y medios, en varones y entre consumidores de drogas inyectables que dieron positivo para el virus de la inmunodeficiencia humana (VIH), así como durante los periodos sin tratamiento. Las sobredosis y el síndrome de la inmunodeficiencia adquirida (SIDA) fueron las causas principales de muerte en las cohortes.Conclusión En comparación con la población general, los consumidores de drogas inyectables presentan un riesgo elevado de muerte, si bien las tasas de mortalidad varían en los distintos lugares. Cualquier enfoque completo para mejorar los resultados sanitarios en este grupo deberá esforzarse por reducir la infección por VIH, así como las otras causas de muerte, en especial, la sobredosis.



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